During carcinogenesis, the disruption of TGF-beta signaling has been shown to be critical. The underlying mechanisms of resistance to the growth inhibitory effect of TGF-beta in malignant cells involve the altered expression of either the receptors or the signaling molecules. Evidence to date, though, suggests that the most prevalent mechanism involves the receptors. The loss of expression of TGF-beta type II receptor in association with resistance to the growth-inhibitory effect of TGF-beta has been reported in various types of cancers, including gastric and colon. Because the loss of TGF-beta type II receptor expression is frequently observed in many different types of cancers, TGF-beta type II receptor has been proposed to be a tumor suppressor. Our studies have led to several important observations of mechanisms which inactivate TGF-beta type II receptor. (i) Transcriptional repression of the TGF-beta type II receptor gene is a major mechanism to inactivate TGF-beta type II receptor. (ii) The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 gene on chromosome 12p13 in frame with the NTRK3 (TrkC) neurotropin-3 receptor gene on chromosome 15q25. The resultant ETV6-NTRK3 fusion protein is detected in several human cancers including congenital fibrosarcoma and the secretory form of human breast cancer. ETV6-NTRK3 transforms NIH3T3 cells and suppresses TGF-beta type II receptor kinase activity through its interaction with TGF-beta type II receptor. Another focus of our research has been to identify the cellular proteins or viral oncoproteins that suppress TGF-beta signaling by targeting the Smad proteins. We have shown that the human T-cell lymphotropic virus-1 (HTLV-1)-Tax, the human papillomavirus (HPV)-E7, and the novel cellular protein EID-2 suppress TGF-beta signaling through interaction with Smad proteins, whereas the hepatitis B virus (HBV)-X amplifies and augments TGF-beta signaling through a direct interaction with signaling intermediate, Smad4. Overepxression of Smad7 is known to suppress TGF-beta signaling. However, the role of Smad7 induced by TGF-beta and other signals is not well characterized. Since Smad7 induces apoptosis independently of TGF-beta signaling and has an intrinsic transcriptional activity, we have attempted to identify the proteins interacting with Smad7 using a yeast two-hybrid screening, and the genes regulated by Smad7 by cDNA microarray. We have shown that Jab1/CSN5, a component of the COP9 signalosome, regulates TGF-beta signaling by binding to Smad7 and promoting its degradation.